Difluoromethylated compounds are becoming more common in the pharmaceutical industry. Illustrative examples of such compounds include eflornithine, an ornithine decarboxylase inhibitor used for treating sleeping sickness; pantoprazole, a proton pump inhibitor used for treating stomach erosion and ulceration; afloqualone, a nicotinic antagonist marketed as a mylorelaxant; and fluticasone propionate, that is used against a wide spectrum of inflammatory conditions. See, Hu et al., Chem. Commun., 7465-7478 (2009).
Contrary to their trifluoromethyl relative, difluoromethyl arenes are relatively understudied. The difluoromethyl group is a highly sought after motif for which chemists currently do not have good routes of access.
Currently, the main method used to prepare difluoromethyl arenes is treatment of the corresponding aldehyde with diethylaminosulfur trifluoride (DAST) or SF4. More recently, Amii and coworkers [Fujikawa et al., Org. Lett., 13(20):5560-5563 (2011)] illustrated that a copper-mediated coupling of CF2H to an iodobenzene could be a possibility.
It was already known that, unlike CF3—, CF2H— complexes with copper are thermally unstable. Therefore, Amii and co-workers adjusted their strategy and focused on first forming a —CF2R bond, then converting CF2R into CF2H. One way to do this was to stabilize the CF2 anion by placing it alpha to a carbonyl. To simplify and enable better control of conditions, they used alpha silyl esters with the general formula R3SiCF2CO2Et. The reaction sequence is illustrated below.

An earlier-reported synthesis utilized potassium (trifluoromethyl)trimethoxyborane as a new source of CF3 nucleophiles in copper-catalyzed trifluoromethylation reactions. The crystalline salt was reported as being stable on storage, easy to handle, and can be obtained in near-quantitative yields simply by mixing B(OMe)3, CF3SiMe3, and KF. This trifluoromethylation reagent also permits the conversion of various aryl iodides into the corresponding benzotrifluorides in high yields under mild, base-free conditions in the presence of catalytic quantities of a CuI/1,10-phenanthroline complex. [Knauber et al., Chem.-Eur. J. 17:2689-2697 (2011).]
Although a step forward, the above reaction sequences still need an alternative concept. One of the inventors and coworkers recently published a new method of adding trifluoromethyl free radicals to aryl heterocycles using Langlois reagent: F3CSO2Na and t-BuOOH in the absence of added metal catalyst. Yields of trifluoromethylated products were reported to be between about 33 and 90 percent. [Ji et al., Pro Natl Acad Sci USA, 108:14411-14415 (2011).]
Attempts to expand that work with a model reactant used in that prior study, caffeine, with F2HCSO2Na and t-BuOOH in the absence of added metal catalyst provided no difluoromethylated product. When F2HCSO2Li was tried in place of F2HCSO2Na, the reaction did not go to completion, although some product was formed. Thus, as noted in their “Conclusions and future directions”, Hu et al., Chem. Commun., 7465-7478 (2009), noted that both electrophilic and free radical di- and monofluoromethylations are less explored compared to nucleophilic di- and monofluoromethylations, and that transition metal-catalyzed (or mediated) di- and monofluoromethylation have rarely been known.
The comments of Hu et al. notwithstanding, further work led to the preparation of a new reagent that is uniquely able to provide difluoromethylation of unsaturated compounds in high yield. The new reaction route serves as a practical process to prepare the unprecedented difluoromethylating agent zinc difluoromethanesulfinate hydrate.